Pancreatitis canresultwhenenzymessecretedbypancreaticacinarcellsbecomeproteolyticallyactivatedbeforetheyhavereachedtheirappropriatesiteofactioninthesmallintestinallumen.Indeed,pancreaticjuicecontainsavarietyoftrypsininhibitorstoreducetheriskofprematureactivation,becausetrypsinistheactivatorofotherpro-formsofenzymessecretedinpancreaticjuice.Asecondlevelofprotectionliesinthefactthattrypsincanbedegradedbyothertrypsinmolecules.Despitethesedefenses,someindividualsaresusceptibletohereditarypancreatitisthatoccursspontaneouslyintheabsenceofknownriskfactors.Insomeofthesepatientsthereisamutationintrypsinthatrendersitresistanttodegradationbyothertrypsinmolecules.Othersharbormutationsintrypsininhibitors,renderingtheinhibitorsinactive.Inanyevent,ifotherdefenseshavebeenbreachedandtrypsinbecomesactiveprematurely,aviciouscycleofenzymeactivationensuesandboutsofpancreatitisfollow.
Characteristics and Control of Ductular Secretion
In this section we consider how the pancreatic ductular cells contribute to the flow and composition of pancreatic juice in the postprandial period. The ducts of the pancreas can be considered the effector arm of a pH regulatory
Lobules of acinar and ductal parenchyma
Secretion of H2O and –
Extralobular HCO3 in response to ductal system absorption of Cl˜ Cl˜
Direction of fluid movement •Fig. 30.2 Locationsofimportanttransportprocessesinvolvedintheelaborationofpancreaticjuice.AcinarfluidisisotonicandresemblesplasmainitsconcentrationsofNa+ ,K+ ,Cl− ,andHCO3− .SecretionofacinarfluidandtheproteinsitcontainsisstimulatedprimarilybyCCK.Thehormonesecretinstimulatessecretionofwaterandelectrolytesfromthecellsthatlinetheextralobularducts.Thesecretin-stimulatedsecretionisricherinHCO3− thantheacinarsecretionbecauseofCl−/HCO3− exchange.(AdaptedfromSwansonCH,SolomonAK.J Gen Physiol 1973;62:407.) system designed to respond to luminal acid in the small intestine and secrete just enough bicarbonate to restore pH to neutrality (
Fig. 30.3 ). This regulatory function also requires mechanisms to sense luminal pH and convey this information to the pancreas as well as other epithelia (e.g., biliary ductules and the duodenal epithelium itself) capable of secreting bicarbonate. The pH-sensing mechanism is embodied in specialized endocrine cells known as S cells, localized within the small intestinal epithelium. When luminal pH falls below approximately 4.5, S cells are triggered to release secretin in response to the increase in [H+]. The components of this regulatory loop constitute a self-limited system. Thus as secretin evokes secretion of bicarbonate, pH in the small intestinal lumen will rise and the signal for release of secretin from S cells will be terminated.
At the cellular level, secretin stimulates epithelial cells to secrete bicarbonate into the ductular lumen, with water following via the paracellular route to maintain osmotic equilibrium. Secretin increases cyclic adenosine monophosphate (cAMP) in the ductular cells and thereby opens cystic fibrosis transmembrane conductance regulator (CFTR) • BOX 30.1 Products of Pancreatic Acinar Cells